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Molecules 2016, 21(9), 1222;

Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China
Author to whom correspondence should be addressed.
Academic Editor: Alessandro Pedretti
Received: 13 July 2016 / Revised: 21 August 2016 / Accepted: 9 September 2016 / Published: 19 September 2016
(This article belongs to the Collection Molecular Docking)
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11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11β-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11β-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11β-HSD1 inhibitors. View Full-Text
Keywords: 11β-HSD1; 3D-QSAR; MESP; MD simulations; binding free energy 11β-HSD1; 3D-QSAR; MESP; MD simulations; binding free energy

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Qian, H.; Chen, J.; Pan, Y.; Chen, J. Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations. Molecules 2016, 21, 1222.

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